3 Biotech (2018) 8:228
Identication of curcumin derivatives as human LMTK3 inhibitors
for breast cancer: a docking, dynamics, and MM/PBSA approach
· S. Jayanthi
Received: 23 June 2017 / Accepted: 2 April 2018 / Published online: 27 April 2018
© Springer-Verlag GmbH Germany, part of Springer Nature 2018
Human lemur tyrosine kinase-3 (LMTK3) is primarily involved in regulation of estrogen receptor–α (ERα) by phosphoryla-
tion activity. LMTK3 acts as key biomarker for ERα positive breast cancer and identiﬁed as novel drug target for breast cancer.
Due to the absence of experimental reports, the computational approach has been followed to screen LMTK3 inhibitors from
natural product curcumin derivatives based on rational inhibitor design. The initial virtual screening and re-docking resulted
in identiﬁcation of top three leads with favorable binding energy and strong interactions in critical residues of ATP-binding
cavity. ADME prediction conﬁrmed the pharmacological activity of the leads with various properties. The stability and
binding aﬃnity of leads were well reﬁned in dynamic system from 25 ns MD simulations. The behavior of protein motion
towards closure of ATP-binding cavity was evaluated based on eigenvectors by PCA. In addition, MM/PBSA calculations also
conﬁrmed the relative binding free energy of LMTK3–lead complexes in favor of the eﬀective binding. From our study, novel
LMTK3 inhibitors tetrahydrocurcumin, curcumin 4,4′-diacetate, and demethoxycurcumin have been proposed with inhibition
mechanism. Further experimental evaluation on reported lead candidates might prove its role in breast cancer therapeutics.
Keywords LMTK3 · Virtual screening · Molecular dynamics simulation · Principal component analysis · Free energy
The human hormone estrogen plays a vital role in breast
cancer growth and cell development (Labrie et al. 1999).
Estrogen receptors (ERs) are the speciﬁc hormone receptor
of estrogen found to be express more in two-thirds of tumor
cells compared to normal breast cells (Robinson et al. 2000).
Among types of breast cancer, the estrogen receptor-α (ERα)
positive breast cancers are very common in metastatic stage
of breast cancer (Stebbing et al. 2011). The development of
endocrine resistance in human is the major bottleneck for
the treatment of ERα positive breast cancer. In case of ERα
positive breast cancer, the protein kinase enzymes are found
to be novel drug target to overcome the endocrine resistance.
Moreover, the kinase inhibitors that target protein kinase
enzymes are considered as eﬀective therapeutic agents for
breast cancer (Giamas et al. 2007).
Human lemur tyrosine kinase-3 (LMTK3) is identiﬁed
as novel drug target for breast cancer with extensive screen-
ing of human genes involved in ERα positive breast cancer.
LMTK3 belongs to protein group of serine/threonine/tyros-
ine kinases family (Robinson et al. 2000). The primary func-
tion of LMTK3 is the regulation of human ERα by phospho-
rylation activity in breast cancer. The key process of LMTK3
exon sequence change between human and chimpanzees
conﬁrmed the major reason for susceptibility of humans to
ERα positive breast cancer (Stebbing et al. 2012). In addi-
tion, LMTK3 also identiﬁed as new potential biomarker for
ERα positive breast cancer with positive selection compared
with chimpanzee ortholog (Giamas et al. 2011). Due to the
critical role of LMTK3 in breast cancer, the design of poten-
tial inhibitors against LMTK3 can downregulate mRNA
expression of ERα and can be successful in breast cancer
treatment in modern era (Johnson and O’Malley, 2011).
Electronic supplementary material The online version of this
article (https ://doi.org/10.1007/s1320 5-018-1239-6) contains
supplementary material, which is available to authorized users.
* S. Jayanthi
Computational Drug Design Lab, Department
of Biotechnology, School of Bio Sciences and Technology,
Vellore Institute of Technology (VIT), Vellore,
TamilNadu 632014, India